Compounds and methods for the treatment of airway diseases and for the delivery of airway drugs

ABSTRACT

Chronic obstructive airway diseases are treated by administering an osmotically active compound such as a salt, sugar, sugar alcohol, or organic osmolyte to the afflicted airway surface. The compound may be administered as a liquid or dry powder aerosol formulation. Diseases that can be treated by the method include cystic fibrosis, chronic bronchitis, and ciliary dyskinesia. The formulations of the invention can also be used in conjunction with other active agents such as bronchodilators, sodium channel blockers, antibiotics, enzymes, or purinoceptor agonists on airway surfaces.

STATEMENT OF PRIORITY

This application is a continuation of U.S. patent application Ser. No.10/087,355, which is a divisional of U.S. patent application Ser. No.09/465,429, filed Dec. 21, 1999, now U.S. Pat. No. 6,926,911, whichclaims priority from U.S. Provisional Patent Application Ser. No.60/137,991 filed Jun. 7, 1999 and from U.S. Provisional PatentApplication Ser. No. 60/113,785 filed Dec. 22, 1998, the disclosures ofall of which are to be incorporated by reference herein in theirentirety.

STATEMENT OF FEDERAL SUPPORT

This invention was made with Government support under Grant No. HL51818from the National Institutes of Health. The United States government hascertain rights in this invention.

FIELD OF THE INVENTION

This invention relates to methods and compositions useful for hydratingairway surfaces.

BACKGROUND OF THE INVENTION

Chronic obstructive pulmonary diseases are characterized by theretention of mucous secretions in the lungs. Examples of such diseasesinclude cystic fibrosis, chronic bronchitis, and primary or secondaryciliary dyskinesia. Such diseases affect approximately 15 millionpatients in the United States, and are the sixth leading cause of death.Other airway or pulmonary diseases characterized by the accumulation ofretained mucous secretions include sinusitis (an inflammation of theparanasal sinuses associated with upper respiratory infection) andpneumonia.

U.S. Pat. No. 5,817,028 to Anderson describes a method for theprovocation of air passage narrowing (for evaluating susceptibility toasthma) and/or the induction of sputum in subjects. It is suggested thatthe same technique can be used to induce sputum and promote mucociliaryclearance. Substances suggested include sodium chloride, potassiumchloride, mannitol and dextrose.

SUMMARY OF THE INVENTION

Certain objects, advantages and novel features of the invention will beset forth in the description that follows, and will become apparent tothose skilled in the art upon examination of the following, or may belearned with the practice of the invention.

A first aspect of the present invention is a method for treating chronicobstructive pulmonary disease in a subject in need of such treatment.The method comprises administering a non-absorbable, osmotically activecompound (hereinafter referred to as an “active compound”) such as asalt, sugar, sugar alcohol, organic osmolyte, or other osmoticallyactive compound to an airway surface of the subject in an amounteffective to increase the volume of fluid on the airway surface.

In one embodiment of the foregoing, a bronchodilator is administered tothe patient prior to or concurrently with the active compound to inhibitbronchoconstriction that may be induced by the active compound.

The active compound may be administered as a delayed or controlledrelease formulation, such as by encapsulating the active compound inliposomes, encapsulating the compound in a biodegradable polymer, etc.

A second aspect of the present invention is a therapeutic method ofadministering an active agent to an airway surface of a subject in needthereof. The method comprises administering the active agent in aneffective therapeutic amount in a vehicle, the vehicle comprising anosmotically active compound of the present invention in an amounteffective to increase the volume of liquid on the airway surface.

A third aspect of the present invention is a method for the lavage ofthe lung of a patient in need thereof. The method comprisesadministering a liquid comprising an active compound of the presentinvention to an afflicted portion of the lung of the patient (e.g., alobe) in an amount effective to wash the afflicted lung portion, theactive compound in the solution being present in an amount effective toincrease the volume of liquid on the airway surface of the portion ofthe lung to which the liquid is administered.

Active compounds of the present invention, used either as activecompounds alone, or as active compounds used in conjunction with otherkinds of active agents (e.g., bronchodilators, purinergic receptors,antibiotics, enzymes, anti-inflammatory agents, etc.), may beadministered to airway surfaces (including nasal surfaces) by anysuitable means, such as by droplets, sprays, aerosols of respirable ornon-respirable particles, or transbronchoscopic lavage. The activecompounds of the present invention may be administered in aqueous ornon-aqueous (e.g., solid particulate) form.

Formulations of the active compounds of the present invention, eitherwith or without other active ingredients for administration to airwaysurfaces, are also an aspect of this invention.

The use of an active compound of the present invention for thepreparation of a medicament for carrying out the methods described aboveare also an aspect of this invention.

One object of the methods and formulations described herein is to expandor increase the volume of fluid on airway surfaces, particularly thevolume of the periciliary liquid layer, and to thereby increase orfacilitate cough clearance, mucociliary clearance, and/or gas-liquiddependent clearance of mucous.

The foregoing and other aspects of the present invention are explainedin detail in the specification set forth below.

DETAILED DESCRIPTION

The present invention now will be described more fully hereinafter, inwhich preferred embodiments of the invention are illustrated. Thisinvention may, however, be embodied in many different forms and shouldnot be construed as limited to the embodiments set forth herein. Rather,these embodiments are provided so that this disclosure will fully conveythe scope of the invention to those skilled in the art. Unless otherwisedefined, all technical and scientific terms used herein have the samemeaning as commonly understood by one of ordinary skill in the art towhich this invention belongs. All publications, patent applications,patents, and other references mentioned herein are incorporated byreference in their entirety.

Active compounds of the present invention are molecules or compoundsthat are osmotically active (i.e., are “osmolytes”). “Osmoticallyactive” compounds of the present invention are membrane-impermeable(i.e., essentially non-absorbable) on the airway or pulmonary epithelialsurface. The terms “airway surface” and “pulmonary surface,” as usedherein, include pulmonary airway surfaces such as the bronchi andbronchioles, alveolar surfaces, and nasal and sinus surfaces. Activecompounds of the present invention may be ionic osmolytes (i.e., salts),or may be non-ionic osmolytes (i.e., sugars, sugar alcohols, and organicosmolytes). It is specifically intended that both racemic forms of theactive compounds that are racemic in nature are included in the group ofactive compounds that are useful in the present invention.

Active compounds useful in the present invention that are ionicosmolytes include any salt consisting of a pharmaceutically acceptableanion and a pharmaceutically acceptable cation. Preferably, either (orboth) of the anion and cation are non-absorbable (i.e., osmoticallyactive and not subject to rapid active transport) in relation to theairway surfaces to which they are administered. Such compounds includebut are not limited to anions and cations that are contained in FDAapproved commercially marketed salts, see, e.g., Remington: The Scienceand Practice of Pharmacy, Vol. II, pg. 1457 (19th Ed. 1995), and can beused in any combination including their conventional combinations.

Pharmaceutically acceptable anions that can be used to carry out thepresent invention include, but are not limited to, acetate,benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calciumedetate, camsylate (camphorsulfonate), carbonate, chloride, citrate,dihydrochloride, edetate, edisylate (1,2-ethanedisulfonate), estolate(lauryl sulfate), esylate (1,2-ethanedisulfonate), fumarate, gluceptate,gluconate, glutamate, glycollylarsanilate(p-glycollamidophenylarsonate), hexylresorcinate, hydrabamine(N,N′-Di(dehydroabietyl)ethylenediamine), hydrobromide, hydrochloride,hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate,maleate, mandelate, mesylate, methylbromide, methylnitrate,methylsulfate, mucate, napsylate, nitrate, pamoate (embonate),pantothenate, phosphate or diphosphate, polygalacturonate, salicylate,stearate, subacetate, succinate, sulfate, tannate, tartrate, teoclate(8-chlorotheophyllinate), triethiodide, bicarbonate, etc. Particularlypreferred anions include sulfate, nitrate, gluconate, iodide,bicarbonate, bromide, and phosphate. In that chloride is absorbed byairway surfaces, it is a less preferred anion.

Pharmaceutically acceptable cations that can be used to carry out thepresent invention include, but are not limited to, organic cations suchas benzathine (N,N′-dibenzylethylenediamine), chloroprocaine, choline,diethanolamine, ethylenediamine, meglumine (N-methyl D-glucamine),procaine, D-Lysine, L-lysine, D-arginine, L-arginine, triethylammonium,N-methyl D-glycerol, and the like. Particularly preferred organiccations are 3-carbon, 4-carbon, 5-carbon and 6-carbon organic cations.Metallic cations useful in the practice of the present invention includebut are not limited to aluminum, calcium, lithium, magnesium, potassium,sodium, zinc, iron, ammonium, and the like. Particularly preferredcations include potassium, choline, lithium, meglumine, D-lysine,ammonium, magnesium, and calcium. In that sodium is absorbed by airwaysurfaces, it is a less preferred cation for the purposes of the presentinvention. As between the dextrorotatory (D) form and the levorotatory(L) form of an active compound of the present invention, the D-form ispreferred.

Specific examples of salts that may be used as active compounds to carryout the present invention include, but are not limited to, potassiumchloride, choline chloride, choline iodide, lithium chloride, megluminechloride, L-lysine chloride, D-lysine chloride, ammonium chloride,potassium sulfate, potassium nitrate, potassium gluconate, potassiumiodide, ferric chloride, ferrous chloride, potassium bromide, etc.Either a single salt or a combination of different salts may be used tocarry out the present invention. Combinations of different salts arepreferred. When different salts are used, one of the anion or cation maybe the same among the differing salts.

Active compounds of the present invention also include non-ionicosmolytes such as sugars, sugar-alcohols, and organic osmolytes. Sugarsand sugar-alcohols useful in the practice of the present inventioninclude but are not limited to 3-carbon sugars (e.g., glycerol,dihydroxyacetone); 4-carbon sugars (e.g., both the D and L forms oferythrose, threose, and erythrulose); 5-carbon sugars (e.g., both the Dand L forms of ribose, arabinose, xylose, lyxose, psicose, fructose,sorbose, and tagatose); and 6-carbon sugars (e.g., both the D and Lforms of altose, allose, glucose, mannose, gulose, idose, galactose, andtalose, and the D and L forms of allo-heptulose, allo-hepulose,gluco-heptulose, manno-heptulose, gulo-heptulose, ido-heptulose,galacto-heptulose, talo-heptulose). Additional sugars useful in thepractice of the present invention include raffinose, raffinose seriesoligosaccharides, and stachyose. Both the D and L forms of the reducedform of each sugar/sugar alcohol useful in the present invention arealso active compounds within the scope of the invention. For example,glucose, when reduced, becomes sorbitol; within the scope of theinvention, sorbitol and other reduced forms of sugar/sugar alcohols(e.g., dulcitol, arabitol) are accordingly active compounds of thepresent invention. As with the ionic osmolytes of the present invention,as between the dextrorotatory (D) form and the levorotatory (L) form ofan active compound of the present invention, the D-form is preferred.

Active compounds of the present invention additionally include thefamily of non-ionic osmolytes termed “organic osmolytes.” The term“organic osmolytes” is generally used to refer to molecules used tocontrol intracellular osmolality in the kidney. See e.g., J. S. Handleret al., Comp. Biochem. Physiol, 117, 301-306 (1997); M. Burg, Am. J.Physiol. 268, F983-F996 (1995). Although the inventor does not wish tobe bound to any particular theory of the invention, it appears thatthese organic osmolytes are useful in controlling extracellular volumeon the airway/pulmonary surface. Organic osmolytes useful as activecompounds in the present invention include but are not limited to threemajor classes of compounds: polyols (polyhydric alcohols), methylamines,and amino acids. The polyol organic osmolytes considered useful in thepractice of this invention include, but are not limited to, inositol,myo-inositol, and sorbitol. The methylamine organic osmolytes useful inthe practice of the invention include, but are not limited to, choline,betaine, carnitine (L-, D- and DL forms), phosphorylcholine,lyso-phosphorylcholine, glycerophosphorylcholine, creatine, and creatinephosphate. The amino acid organic osmolytes of the invention include,but are not limited to, the D- and L forms of glycine, alanine,glutamine, glutamate, aspartate, proline and taurine. Additionalosmolytes useful in the practice of the invention include tihulose andsarcosine. Mammalian organic osmolytes are preferred, with human organicosmolytes being most preferred. However, certain organic osmolytes areof bacterial, yeast, and marine animal origin, and these compounds arealso useful active compounds within the scope of the present invention.

Under certain circumstances, an osmolyte precursor may be administeredto the subject; accordingly, these compounds are also useful in thepractice of the invention. The term “osmolyte precursor” as used hereinrefers to a compound which is converted into an osmolyte by a metabolicstep, either catabolic or anabolic. The osmolyte precursors of thisinvention include, but are not limited to, glucose, glucose polymers,glycerol, choline, phosphatidylcholine, lyso-phosphatidylcholine andinorganic phosphates, which are precursors of polyols and methylamines.Precursors of amino acid osmolytes within the scope of this inventioninclude proteins, peptides, and polyamino acids, which are hydrolyzed toyield osmolyte amino acids, and metabolic precursors which can beconverted into osmolyte amino acids by a metabolic step such astransamination. For example, a precursor of the amino acid glutamine ispoly-L-glutamine, and a precursor of glutamate is poly-L-glutamic acid.

Also intended within the scope of this invention are chemically modifiedosmolytes or osmolyte precursors. Such chemical modifications involvelinking to the osmolyte (or precursor) an additional chemical groupwhich alters or enhances the effect of the osmolyte or osmolyteprecursor (e.g., inhibits degradation of the osmolyte molecule). Suchchemical modifications have been utilized with drugs or prodrugs and areknown in the art. (See, for example, U.S. Pat. Nos. 4,479,932 and4,540,564; Shek, E. et al., J. Med. Chem. 19:113-117 (1976); Bodor, N.et al., J. Pharm. Sci. 67:1045-1050 (1978); Bodor, N. et al., J. MedChem. 26:313-318 (1983); Bodor, N. et al., J. Pharm. Sci. 75:29-35(1986);

In general, osmotically active compounds of the present invention (bothionic and non-ionic) that do not promote, or in fact deter or retardbacterial growth are preferred.

The active compounds, methods and compositions of the present inventionare useful as therapeutics for the treatment of chronic obstructiveairway or pulmonary disease in subjects in need of such treatment. Theactive compounds, compositions and methods described herein may also beused to induce the production of a sputum or mucous sample in a patient.Additionally, the active compounds, compositions and methods describedherein can be used for the lavage of the lungs and/or airways of apatient. The active compounds and compositions described herein may alsobe administered with other active agents that are to be introduced intoairways of a subject, and in fact may function as vehicles or carriersfor the other active agents.

Suitable subjects to treated according to the present invention includeboth avian and mammalian subjects, preferably mammalian. Any mammaliansubject in need of being treated according to the present invention issuitable, including dogs, cats and other animals for veterinarypurposes. Human subjects are preferred. Human subjects of both gendersand at any stage of development (i.e., neonate, infant, juvenile,adolescent, adult) can be treated according to the present invention.Preferred subjects include those humans afflicted with a chronicobstructive airway or pulmonary disease, including but not limited tocystic fibrosis, chronic bronchitis, emphysema, primary and secondaryciliary dyskinesia, sinusitis, and pneumonia. Human subjects afflictedwith cystic fibrosis are particularly preferred.

Active compounds disclosed herein may be administered to airway surfacesincluding the nasal passages, sinuses and lungs of a subject by anysuitable means known in the art, such as by nose drops, mists, etc. Inone embodiment of the invention, the active compounds of the presentinvention are administered by transbronchoscopic lavage. In a preferredembodiment of the invention, the active compounds of the presentinvention are deposited on lung airway surfaces by administering anaerosol suspension of respirable particles comprised of the activecompound, which the subject inhales. The respirable particles may beliquid or solid. Numerous inhalers for administering aerosol particlesto the lungs of a subject are known.

Inhalers such as those developed by Inhale Therapeutic Systems, PaloAlto, Calif., USA, may be employed, including but not limited to thosedisclosed in U.S. Pat. Nos. 5,740,794; 5,654,007; 5,458,135; 5,775,320;and 5,785,049. The Applicant specifically intends that the disclosuresof all patent references cited herein be incorporated by referenceherein in their entirety. Inhalers such as those developed by DuraPharmaceuticals Inc, San Diego, Calif., USA, may also be employed,including but not limited to those disclosed in U.S. Pat. Nos.5,622,166; 5,577,497; 5,645,051; and 5,492,112. Additionally, inhalerssuch as those developed by Aradigin Corp., Hayward, Calif., USA, may beemployed, including but not limited to those disclosed in U.S. Pat. Nos.5,826,570; 5,813,397; 5,819,726; and 5,655,516. These apparatuses areparticularly suitable as dry particle inhalers.

Aerosols of liquid particles comprising the active compound may beproduced by any suitable means, such as with a pressure-driven aerosolnebulizer or an ultrasonic nebulizer. See, e.g., U.S. Pat. No.4,501,729. Nebulizers are commercially available devices which transformsolutions or suspensions of the active ingredient into a therapeuticaerosol mist either by means of acceleration of compressed gas,typically air or oxygen, through a narrow venturi orifice or by means ofultrasonic agitation. Suitable formulations for use in nebulizersconsist of the active ingredient in a liquid carrier, the activeingredient comprising up to 40% w/w of the formulation, but preferablyless than 20% w/w. The carrier is typically water (and most preferablysterile, pyrogen-free water) or a dilute aqueous alcoholic solution.Perfluorocarbon carriers may also be used. Optional additives includepreservatives if the formulation is not made sterile, for example,methyl hydroxybenzoate, antioxidants, flavoring agents, volatile oils,buffering agents and surfactants.

Aerosols of solid particles comprising the active compound may likewisebe produced with any solid particulate medicament aerosol generator.Aerosol generators for administering solid particulate medicaments to asubject produce particles which are respirable, as explained above, andgenerate a volume of aerosol containing a predetermined metered dose ofa medicament at a rate suitable for human administration. Oneillustrative type of solid particulate aerosol generator is aninsufflator. Suitable formulations for administration by insufflationinclude finely comminuted powders which may be delivered by means of aninsufflator or taken into the nasal cavity in the manner of a snuff. Inthe insufflator, the powder (e.g., a metered dose thereof effective tocarry out the treatments described herein) is contained in capsules orcartridges, typically made of gelatin or plastic, which are eitherpierced or opened in situ and the powder delivered by air drawn throughthe device upon inhalation or by means of a manually-operated pump. Thepowder employed in the insufflator consists either solely of the activeingredient or of a powder blend comprising the active ingredient, asuitable powder diluent, such as lactose, and an optional surfactant.The active ingredient typically comprises from 0.1 to 100% w/w of theformulation. A second type of illustrative aerosol generator comprises ametered dose inhaler. Metered dose inhalers are pressurized aerosoldispensers, typically containing a suspension or solution formulation ofthe active ingredient in a liquified propellant. During use thesedevices discharge the formulation through a valve adapted to deliver ametered volume, typically from 10 to 150 μl, to produce a fine particlespray containing the active ingredient. Suitable propellants includecertain chlorofluorocarbon compounds, for example,dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane and mixtures thereof. The formulation mayadditionally contain one or more co-solvents, for example, ethanol,surfactants, such as oleic acid or sorbitan trioleate, antioxidants andsuitable flavoring agents.

The aerosol, whether formed from solid or liquid particles, may beproduced by the aerosol generator at a rate of from about 10 to 150liters per minute, more preferably from about 30 to 150 liters perminute, and most preferably about 60 liters per minute. Aerosolscontaining greater amounts of medicament may be administered morerapidly.

The dosage of the active compounds disclosed herein will vary dependingon the condition being treated and the state of the subject, butgenerally may be from about 0.1 or 1 to about 30, 50 or 100 milliosmolesof the salt, deposited on the airway surfaces. The daily dose may bedivided among one or several unit dose administrations.

Other active agents may be administered concurrently to the subject inneed thereof with the osmotically active compounds of the presentinvention. As used herein, the term “concurrently” means sufficientlyclose in time to produce a combined effect (that is, concurrently may besimultaneously, or it may be two or more events occurring within a shorttime period before or after each other). When administered with otheractive agents, the active compounds of the present invention mayfunction as a vehicle or carrier for the other active agent, or maysimply be administered concurrently with the other active agent. Theactive compound of the present invention may be used as a dry or liquidvehicle for administering other active ingredients to airway surfaces.Such other active agents may be administered for treating the disease ordisorder for which they are intended, in their conventional manner anddosages, in combination with the active compounds of the presentinvention, which may be thought of as serving as a vehicle or carrierfor the other active agent. Any such other active ingredient may beemployed, particularly where hydration of the airway surfaces (i.e., theactivity of the osmotically active compounds of the present invention)facilitates the activity of the other active ingredient (e.g., byfacilitating or enhancing uptake of the active ingredient, bycontributing to the mechanism of action of the other active ingredient,or by any other mechanisms). In a preferred embodiment of the invention,when the active compound of the present invention is administeredconcurrently with another active agent, the active compound of thepresent invention has an additive effect in relation to the other activeagent; that is, the desired effect of the other active agent is enhancedby the concurrent administration of the active compounds of the presentinvention.

In particular, bronchodilators may be administered concurrently with theactive compounds of the present invention. Bronchodilators that can beused in the practice of the present invention include, but are notlimited to, β-adrenergic agonists including but not limited toepinephrine, isoproterenol, fenoterol, albutereol, terbutaline,pirbuterol, bitolterol, metaproterenol, isoetharine, salmeterol,xinafoate, as well as anticholinergic agents including but not limitedto ipratropium bromide, as well as compounds such as theophylline andaminophylline. These compounds may be administered in accordance withknown techniques, either prior to or concurrently with the activecompounds described herein.

Other active ingredients that may be administered with the activecompounds of the present invention include ion transport modulators andother active agents known to be useful in the treatment of the subjectafflicted with a chronic obstructive pulmonary disease (e.g., DNase,antibiotics, etc.).

Ion transport modulators that can be administered as active agents alongwith the active compounds of the present invention herein include,sodium channel blockers such as amiloride, benzamil or phenamil,purinoceptor (particularly P2Y₂) receptor agonists such as UTP, UTP-γ-S,dinucleotide P2Y₂ receptor agonists, and β-agonists. Thus the method ofthe present invention may be used as a vehicle system to administer theactive compounds described in U.S. Pat. No. 5,837,861 to Pendergast etal., U.S. Pat. No. 5,635,160 to Stutts et al., U.S. Pat. No. 5,656,256to Boucher et al., U.S. Pat. No. 5,292,498 to Boucher et al., and U.S.Pat. No. 4,501,729 to Boucher et al., the disclosures of all of whichare to hereby incorporated by reference herein in their entirety.

Other active ingredients that can be administered in combination withthe formulations described herein include nucleic acids oroligonucleotides; viral gene transfer vectors (including adenovirus,adeno-associated virus, and retrovirus gene transfer vectors); enzymes;and hormone drugs or physiologically active proteins or peptides such asinsulin, somatostatin, oxytocin, desmopressin, leutinizing hormonereleasing hormone, nafarelin, leuprolide, adrenocorticotrophic hormone,secretin, glucagon, calcitonin, growth hormone releasing hormone, growthhormone, etc. Enzyme drugs that may be used to carry out the presentinvention, include but are not limited to DNAse (for the treatment of,e.g., cystic fibrosis), α₁-antitrypsin (e.g., to inhibit elastase in thetreatment of emphysema), etc. Suitable anti-inflammatory agents,including steroids, for use in the methods of the present inventioninclude, but are not limited to, beclomethasone dipropionate,prednisone, flunisolone, dexamethasone, prednisolone, cortisone,theophylline, albuterol, cromolyn sodium, epinephrine, flunisolide,terbutaline sulfate, alpha-tocopherol (Vitamin E),dipalmitoylphosphatidylcholine, salmeterol and fluticasone dipropionate.Examples of antibiotics that may be employed include, but are notlimited to tetracycline, choramphenicol, aminoglycosides, for example,tobramycin, beta-lactams, for example ampicillin, cephalosporins,erythromycin and derivatives thereof, clindamycin, and the like.Suitable anti-viral agents include acyclovir, ribavirin, ganciclovir andfoscarnet. Suitable anti-neoplastic agents include, but are not limitedto, etoposid, taxol, and cisplatin. Antihistamines include, but are notlimited to, diphenhydramine and ranitadine. Anti-Pneumocystis cariniipneumonia drugs such as pentamidine and analogs thereof may also beused. Anti-tuberculosis drugs such as rifampin, erythromycin,chlorerythromycin, etc. Chelators of divalent cations (e.g., EGTA,EDTA), expectorants, and other agents useful in the loosening of mucoussecretions (e.g., n-acetyl-L-cysteine) may also be administered asdesired in the practice of the present invention.

The present invention is particularly useful for chronic treatments:that is, treatments wherein the administration is repeated two or moretimes in close proximity to one another, so that the multiple treatmentsachieve a combined therapeutic effect. For example, the administrationmay be carried out two, three, four, five, six or seven times a week, onseparate days throughout the week. The treatment may be carried out fora period of two, four, or six days or more; daily for two or four weeksor more; daily for two or four months or more. etc. For example, theadministering step may be carried out three, four, five or six times aday for the duration of the condition being treated, with chronicconditions receiving chronic treatments.

The compounds, compositions and methods described herein can be used forthe lavage of a lung, or lung lobe, in a patient in need thereof byadministering an effective therapeutic amount of the compositions to thelung of a subject. Lavage may be carried out with a bronchoscope byinstilling a volume of fluid into a desired lobe of the lung (e.g., 30milliliters to 3 liters, typically 300 milliliters) in accordance withknown techniques. Lavage may be single administration or repetitive(e.g., three washings). A portion of the instilled fluid is removed oraspirated, after instillation, in accordance with known techniques. Thelavage solution may be an aqueous solution, or may be a perfluorocarbonliquid such as used for blood substitutes.

Solid or liquid particulate pharmaceutical formulations containingactive compounds of the present invention should include particles ofrespirable size: that is, particles of a size sufficiently small to passthrough the mouth and larynx upon inhalation and into the bronchi,bronchioles, and (if necessary) the alveoli of the lungs. Thebronchioles are a particularly preferred target for delivery to theairway surfaces. In general, particles ranging from about 1 to 5 or 6microns in size (more particularly, less than about 4.7 microns in size)are respirable. Particles of non-respirable size which are included inthe aerosol tend to be deposited in the throat and swallowed, and thequantity of non-respirable particles in the aerosol is preferablyminimized. For nasal administration, a particle size in the range of10-500 μm is preferred to ensure retention in the nasal cavity.

In the manufacture of a formulation according to the invention, activecompounds of the present invention may be admixed with, inter alia, anacceptable carrier. The carrier must, of course, be acceptable in thesense of being compatible with any other ingredients in the formulationand must not be deleterious to the patient. The carrier may be a solidor a liquid, or both, and is preferably formulated with the compound asa unit-dose formulation, for example, a capsule, which may contain from0.5% to 99% by weight of the active compound. One or more activecompounds may be incorporated in the formulations of the invention,which formulations may be prepared by any of the well-known techniquesof pharmacy consisting essentially of admixing the components.

Compositions containing respirable dry particles of active compound maybe prepared by grinding the active compound with a mortar and pestle,and then passing the micronized composition through a 400 mesh screen tobreak up or separate out large agglomerates.

The pharmaceutical composition may optionally contain a dispersant whichserves to facilitate the formation of an aerosol. A suitable dispersantis lactose, which may be blended with the active agents in any suitableratio (e.g., a 1 to 1 ratio by weight).

The foregoing is illustrative of the present invention, and is not to beconstrued as limiting thereof. The invention is defined by the followingclaims, with equivalents of the claims to be included therein.

1-29. (canceled)
 30. A method of treating chronic obstructive pulmonarydisease in a subject in need of such treatment, comprising administeringat least one osmotically active compound to an airway surface of thesubject in an amount effective to increase the volume of liquid on theairway surface, wherein the at least one osmotically active compoundcomprises at least one salt comprising: (a) a pharmaceuticallyacceptable anion selected from the group consisting of acetate,benzenesulfonate, benzoate, bitartrate, bromide, calcium edetate,camsylate, carbonate, chloride, citrate, dihydrochloride, edetate,edisylate, estolate, esylate, fumarate, gluceptate, gluconate,glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine,hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate,lactate, lactobionate, malate, maleate, mandelate, mesylate,methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate,pamoate, pantothenate, phosphate or diphosphate, polygalacturonate,salicylate, stearate, subacetate, succinate, sulfate, tannate, tannate,teoclate and triethiodide; and (b) a pharmaceutically acceptable cationselected from the group consisting of benzathine, chloroprocaine,choline, diethanolamine, ethylenediamine, meglumine, procaine, D-Lysine,L-lysine, D-arginine, L-arginine, uiethylammonium, N-methyl Do glycerol,aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, iron,and ammonium.
 31. The method according to claim 30, wherein the subjectis afflicted with one or more chronic obstructive pulmonary diseasesselected from the group consisting of cystic fibrosis, chronicbronchitis and ciliary dyskinesia.
 32. The method according to claim 30,wherein the airway surface is a pulmonary airway surface.
 33. The methodaccording to claim 30, wherein the airway surface is a nasal airwaysurface or sinus airway surface.
 34. The method according to claim 30,wherein said administering step of the at least one osmotically activecompound is an aerosol inhalation administering step.
 35. The methodaccording to claim 30, wherein said at least one salt comprises: ananion selected from the group consisting of sulfate, nitrate, gluconate,iodide, chloride, bromide, and phosphate; and a cation selected from thegroup consisting of choline, lithium, meglumine, D-lysine, ammonium,sodium, magnesium calcium, and potassium.
 36. The method according toclaim 30, wherein said at least one salt is sodium chloride.
 37. Themethod according to claim 30, wherein said at least one salt is sodiumnitrate.
 38. The method according to claim 30, wherein the methodfurther comprises administering a bronchodilator to said subject priorto or concurrently with said at least one osmotically active compound inan amount sufficient to inhibit bronchoconstriction.
 39. The method ofclaim 38, wherein the bronchodilator is selected from the groupconsisting of 1-adrenergic agonists, anticholinergic agonists andxanthine derivatives.
 40. The method according to claim 39, wherein theβ-adrenergic agonist is epinephrine, isoproterenol, albuterol,terbutaline, pirbuterol, metaproteronol or salmeterol.
 41. The methodaccording to claim 30, wherein the method further comprisesadministering agents selected from the group consisting of an enzymedrug, an anti-inflammatory agent, an antibiotic, an antiviral agent, ananti-neoplastic agent, an antihistamine, an anti-pneumocystis cariniipneumonia agent, an anti-tuberculosis agent, an expectorant and achelator of divalent cations.
 42. The method according to claim 41,wherein the enzyme drug is DNase or α₁-antitrypsin.
 43. The methodaccording to claim 41, wherein the antibiotic is tetracycline,choramphenicol, an aminoglycosides, a beta-lactam, a cephalosporin,erythromycin or clindamycin.